Recent studies in molecular biology have shown that the cellular signal transduction pathway by the action of Protein Tyrosine Kinases (PTKs) plays a highly important role in tumorigenesis and development of tumors. Inhibition of tyrosine kinase activity can reduce activation of the cellular signal transduction pathway, so as to inhibit tumor cells from inducing survival and proliferation and produce an effect of treating cancers.
Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase that belongs to the insulin receptor superfamily and plays an important role in tumor cell growth and development. The ALK gene may be fused with a variety of protein genes to express the ALK protein, and can have variations such as mutation and amplification. The oncogenic recombination of ALK gene on the short arm of Chromosome 2 in anaplastic large-cell lymphoma (ALCL) was described first in 1997, and later found in other malignancies, including diffuse large B-cell lymphoma and malignant histiocytosis, and also in many parenchymal tumors, including inflammatory myofibroblastoma, esophageal squamous epithelia cell carcinoma, neuroblastoma, and the recently proposed non-small cell lung cancer (NSCLC).
It was first reported in 2007 that the ALK gene may be fused to the EML4 gene to encode and produce ALK, thereby promoting lung cancer cell growth. The EML4-ALK fusion is caused by an insertion into the short arm of Chromosome 2, and so far a number of variants have been discovered. After testing, all of these fused genes were found to have biological functions, and their expression products are a kind of chimeric tyrosine kinase, which have been increasingly involved in reports on NSCLC since 2007.
Based on the discovery of the EML4-ALK fused gene and the distinct effect of ALK inhibitors displayed in the subgroup of population carrying it, NSCLC was divided into different subtypes according to different molecular pathologies, such as the EGFR mutant-, KRAS mutant-, and EML4-ALK gene fusion-types. In general NSCLC patients, the positive rate of the EML4-ALK fused gene is as low as about 3% to 7%. The EML4-ALK fused gene is mainly found in pulmonary adenocarcinoma of non-smokers. A study reported in 2010 showed that, in Chinese patients with pulmonary adenocarcinoma, the positive rate of the EML4-ALK fused gene, 16.13%, was significantly higher than that in Europe and United States; in pulmonary adenocarcinoma of non-smokers, the positive rate was 19.23%; and in pulmonary adenocarcinomas without EGFR or KRAS mutation, its mutation rate was as high as 42.8%.
Although a large number of compounds showing inhibitory activities against protein kinases have been investigated and some protein kinase inhibitors have been marketed for anti-tumor treatment, they can cause drug resistance. Therefore, there is an urgent need to develop new protein kinase inhibitors, for example, ALK inhibitors, for prophylaxis, alleviation and/or treatment of cancers mediated by protein kinases (e.g, ALK), such as ALK-positive non-small cell lung cancer (NSCLC).
WO2014117718 discloses 5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)-4′-methoxy-6′-((S)-2-methylpiperazin-1-yl)-3,3′-bipyridin-6-amine (hereinafter, referred to as the compound of Formula I) and a method for preparation thereof.

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